Film coating

ABSTRACT

A film coating composition suitable for use in coating pharmaceutical formulations comprising: a) an acrylic polymer, which is Eudragit® NE30D, b) an anti-sticking agent, which is glyceryl monostearate (GMS), c) a surface active agent wherein the surface active agent is in an amount less than 1.3% by weight of the dispersion, and d) a water-containing liquid, wherein the dispersion does not contain a vinyl acetate polymer.

FIELD OF THE INVENTION

The present invention relates to a new film coating. More specificallythe present invention relates to a new film coating for the achievementof modified release from pharmaceutical formulations such as tablets,pellets, etc., wherein the film coating may be applied in asubstantially aqueous environment. Furthermore, the invention provides aprocess for the preparation of such a film coating.

BACKGROUND OF THE INVENTION

Oral administration of a drug is the most convenient for the patient.Oral formulations must also meet the requirements of safety andsimplicity. Depending on the drug properties and the therapeuticrequirements, different approaches are taken during its formulation toobtain a suitable drug delivery profile. For example, a sparinglysoluble drug which is given once a day requires a different type offormulation than an easily soluble drug which is taken several times aday.

Different formulations can have different mechanisms for controlling therelease of the active drug. In the thesis by Sandberg 1994,extended-release (ER) formulations of different types of drugs werereviewed. It was concluded that in principle two types of ER dosageforms exist: (i) the matrix system where the drug is mixed with thematrix material (often a polymer or a wax) and (ii) the drug reservoirsystem where the drug is formulated into a core (tablet or pellets)surrounded by a polymeric film. The film coating is then a releaserate-controlling barrier determined by many factors including itsdissolution rate, its permeability, the solubility of the substance,etc.

From a flexibility point of view the formulation of a drug into smalldiscrete units coated with a film has gained much intention. Such aformulation shows several interesting features such as flexibility indosage and release properties. In addition, tablets made from thesediscrete units are easily divisable. In a numbers of studies it wasshown that safe, simple and convenient therapy can be achieved utilizingthis principle for the (water soluble) drug metoprolol and its salts(Ragnarsson et al, Drug Develop Ind Pharmacy 13, 1495 (1987); Sandberget al, Eur 3 Clin Pharmacol 33, S3 (1988) and S9 (1988); Ragnarsson etal, Int J Pharmaceuticl 79, 223 (1992); Sandberg et al, Ibid 68, 167(1991); Sandberg et al, Pharmaceuticl Res 10, 28 (1993); Sandberg et al,Drug Invest 6, 320 (1993); Sandberg, Thesis Uppsala University, (1994).

The formulation of metoprolol into pellets according to the abovementioned references utilized a film coating sprayed from a solutioncontaining a mixture of different celluloses in an organic solvent.However, for environmental reasons it would be preferable to use waterbased film-forming systems for this and other drugs to be formulated aspellets systems. Thus, much effort has been directed to find suitablewater based systems for film coating in drug delivery systems.

Latex particles in water as the dispersion medium have been known foralmost half a century. These particles are polymeric colloidal particlesin the 10 to 100 nm range and have been utilized as film formers indifferent applications. If the polymer particle has a sufficiently lowglass transition temperature (Tg) when the water is evaporated, theparticles can coalesce to form a film. Further development has givenseveral other products that have been tested and reported in a number ofpublications (Petereit and Weisbrod, Eur J Pharmaceutics and Biopharm47, 15 (1999); Petereit et al, Ibid, 41, 219 (1995); Amighi and Moës,STP Pharma Sci 7, 141 (1997); Bodmeier and Paeratukul, Pharm Res 11, 882(1994); Ozturk et al, J Controlled Release 14, 203 (1990). Goodhart etal, Pharmaceutical Tech April, 64 (1984); Bodmeier and Paeratakul Int JPharmceutics 152, 17 (1997); Bodmeier and Paeratakul Drug Develop IndPharmacy 20, 1517 (1994)).

From these and other studies it can be concluded that one of the moreinteresting dispersions, due to the low Tg of the latex polymer and highelongation, is Eudragit® NE 30D, which contains approximately 28.5% w/wparticles of the copolymer poly(ethylacrylate-co-methylmethacrylate),and 1.5% w/w of the non-ionic tenside Nonoxynol 100 (a polyoxyethylatednonylphenol) as a stabiliser. The advantages of this copolymer are thatno plasticizer is needed for film formation, the copolymer has a lowfilm forming temperature and the high flexibility of dried films. Thelast property is especially useful when preparing tablets. However, toobtain best spraying conditions and technical performance, ananti-sticking agent has to be added to the dispersion, as reported byPetereit and Weisbrod 1995, due to the tacky property of the pelletsduring coating. Several such agents are available e.g., talc, silica,magnesium stearate and glyceryl mono stearate (GMS). It was reported,however, that best performance of the dispersion during spraying and ofthe dried film was obtained when the GMS was dispersed with an extrasurface active agent, e.g., Polysorbate 80 (PS80). The reason for addingPS80 is to be able to make a stabile dispersion between GMS and PS80 andto make a dispersion that has a small particle size distribution.

We have found that it has been difficult to obtain results withacceptable reproducibility with respect to, e.g., release rates andstability during storage from formulations manufactured according tothese suggested procedures. It is important that the release profile isstable during the shelf life of the product and also stable in differentenviroments.

Instabilities of coated dosage (water based) forms are mainly based onphysical interaction caused, most likely, by improper formulations ofcoating suspension (i.e., plasticizers, surfactants, or pigments), orthe film coating process (Petereit et al, Eur. J pharmaceutics andBiopharmaceutics 47, (1999) 15-25). Residual moisture, probably enclosedin the core and, migrating over time, may increase the permeability ofcoatings due to plasticizing effects. This increased permeability canalso be due to migration of components in the film coat during storagein different climates, thus resulting in a coating which exhibitsaltered release properties

-   Eur J Pharm Biopharm 41 (4) (1995) 219-228 by Petereit et al    discloses the use of GMS as a glidant in aqueous film coating    formulations comprising Eudragit® L 30 D-55, NE 30D, RL 30D and RS    30D.-   Eur J Pharm Biopharm 47 (1999) 73-78 by Wesseling et al discusses    how reduced tackiness of NE30D films is obtained by the addition of    an anti-tacking agent, e g GMS. This is achieved by the addition of    GMS in an emulsion form that is obtained by mixing a surfactant (e g    Tween 80) with the GMS.-   Eur J Pharm Biopharm 1999, 14 (6) p743-751 by Petereit, Weisbrod is    a review article that gives compositions of dispersions for film    formation in tables. However, nothing is said about how the    additives, e g anti-tacking agents, are added.-   AAPS Pharmasci 2001 3(2) 1-11 by Lin et al discloses that the    endogenous surfactant of NE30D, nonoxynol 100, crystallizes in films    of NE30D. The importance of compensating for this tendency for    crystallization is discussed.-   J Microencapsulation 1997, vol 14, no 6, p743-751 by Mathir et al    discloses coatings comprising NE30D, talc and PEG 6000.-   U.S. Pat. No. 5,817,776 discloses that a dispersion of    lubricant/glidant is formed in water with the help of an “antifoam    suspension”.-   U.S. Pat. No. 5,478,573 discloses that mixtures of different    dispersions are prepared and stabilized with the surface active    agent sodium lauryl sulfate. Also disclosed is a coating comprising    magnesium stearate dispersed in water and added to a mixture of the    two dispersions NE30D and Aquacoat™.-   U.S. Pat. No. 4,784,858 discloses that the anti-tacking agent talc    is added together with a surfactant (Tween 80) to Eudragit E30D.-   WO 02058677 discloses coating formulations comprising sodium stearyl    fumarate (PRUV®).

PURPOSE OF THE INVENTION

The purpose of the present invention is to provide a new film coatingsystem that does not have the above mentioned problems. Improvedproperties of the new film coating system are, for example,non-stickiness, high mechanical strength, reproducibility duringprocessing, and stability of the film coating during storage.

SUMMARY OF THE INVENTION

We have surprisingly found a novel film coating composition whichprovides a latex dispersion suitable for coating pharmaceuticalformulations wherein the film produced serves as a barrier giving closeto constant release (zero-order) from the formulation. In addition, thephysical properties of the film produced no processing problems, such asaggregation of particles; the film exhibited high mechanical strength;and the film was stable exhibiting no change in release properties as aresult of storage. Moreover, the film could be reproducibly made havingthese improved properties.

Accordingly, the invention features a film coating composition, a filmcoating, a formulation including a pharmaceutically core comprising apharmaceutically active agent (e.g., metoprolol) and a film coat. Theinvention further includes a process of making the coating and a processto prepare a formulation having the coating of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a film coating which, has the unexpectedproperty of having a stable release profile following storage.Specifically, the present invention features a pharmaceuticalcomposition which surprisingly has a low amount of surface active agent.

Accordingly, the invention provides a film coating composition suitablefor use in coating pharmaceutical formulations comprising a dispersionwhich comprises:

-   a) an acrylic polymer, which is Eudragit® NE30D-   b) an anti-sticking agent, which is glyceryl monostearate (GMS)-   c) a surface active agent wherein the surface active agent is in an    amount less than 1.3% by weight of the dispersion, and-   d) a water-containing liquid,    wherein the dispersion does not contain a vinyl acetate polymer.

In another aspect, the invention provides a film coat covering apharmaceutical core wherein the core includes a pharmacologically activeingredient and optionally one or more pharmaceutically acceptableexcipients. The film coat includes an:

-   a) an acrylic polymer, which is Eudragit® NE30D-   b) an anti-sticking agent; which is glyceryl monostearate (GMS) and-   c) a surface active agent wherein the surface active agent is in the    amount less than 5.4% by weight of the weight of the film coat, and    wherein the film coat has been deposited from a water-containing    liquid and does not contain a vinyl acetate polymer. In one    embodiment, the acrylic polymer can be an ethyl acrylate and/or    methyl methacrylate copolymer, the anti-sticking agent can be    glyceryl mono stearate (GMS), and the surface active agent can be    nonoxynol 100. Suitably the film coat has a thickness in the range    of 1 to 100 micrometres, preferably in the range of 5 to 50    micrometres and more preferably in the range of 10 to 30 micrometres

The pharmacologically active ingredient can be provided in a pluralityof beads, optionally containing one or more pharmaceutically acceptableexcipients, wherein each of the beads is coated with a film coat asdefined above. Such film coated beads may be provided in sachets orformulated as a capsule, for example a hard gelatin capsule, orcompressed to form tablets using known methods with the optionaladdition of other pharmaceutically acceptable additives. Coated beads tobe compressed into a tablet are obtained by conventional techniquesknown to those skilled in the art. Also, during this process suitableother agents can be added. For example, during the tabletting stepsuitable fillers, e.g., microcrystalline cellulose, talc, sodium stearylfumarate, etc., can be utilised to give acceptable compressioncharacteristics of the formulation, e.g., hardness of the tablet.

Optionally the beads may contain an insoluble core onto which the activeingredient has been deposited, for example, by spraying. Suitablematerials for the inert core are silicon dioxide, glass or plastic resinparticles. Suitable types of plastic material are pharmaceuticallyacceptable plastics such as polypropylene or polyethylene preferablypolypropylene. Such insoluble cores have a size diameter in the range of0.01-2 mm, preferably in the range of 0.05-0.5 mm and more preferably inthe range of 0.1-0.3 mm.

In one embodiment, the ductility of the film can be in a range of500-20000 J/m³, In another embodiment the ductility is in the range of2500-20000 J/m³. In yet another embodiment the ductility is in the rangeof 10000-20000 J/m³.

In another aspect, the invention provides a pharmaceutical formulationwhich includes

-   a) a pharmaceutical core comprising a pharmacologically active    ingredient and optionally one or more pharmaceutically acceptable    excipients, and-   b) a film coat comprising:    -   i) an acrylic polymer, which is Eudragit® NE30D    -   ii) an anti-sticking agent, which is glyceryl monostearate (GMS)    -   iii) a surface active agent wherein the surface active agent is        in the amount less than 5.4% by weight of the weight of the film        coat,        wherein the film coat has been deposited from a water-containing        liquid and does not contain a vinyl acetate polymer.

The pharmacologically active ingredient can be provided in a pluralityof beads, optionally containing one or more pharmaceutically acceptableexcipients, wherein each of the beads is coated with a film coat asdefined above. Such film coated beads may be provided in sachets orformulated as a capsule, for example a hard gelatin capsule, orcompressed to form tablets using known methods with the optionaladdition of other pharmaceutically acceptable additives. Coated beads tobe compressed into a tablet are obtained by conventional techniquesknown to those skilled in the art. Also, during this process suitableother agents can be added. For example, during the tabletting stepsuitable fillers, e.g., microcrystalline cellulose, talc, etc., can beutilised to give acceptable compression characteristics of theformulation, e.g., hardness of the tablet. Suitably the beads have adiameter in the range of 0.01-2 mm, preferably in the range of 0.05-11.0mm and more preferably in the range of 0.1-0.7 mm.

Optionally the beads may contain an insoluble core onto which the activeingredient has been deposited, for example, by spraying. Suitablematerials for the inert core are silicon dioxide, glass or plastic resinparticles. Suitable types of plastic material are pharmaceuticallyacceptable plastics such as polypropylene or polyethylene preferablypolypropylene. Such insoluble cores have a size diameter in the range of0.01-2 mm, preferably in the range of 0.050.5 mm and more preferably inthe range of 0.1-0.3 mm.

In one embodiment, the ductility of the film can be in a range of500-20000 J/m³ In another embodiment the ductility is in the range of2500-20000 J/m³. In yet another embodiment the ductility is in the rangeof 10000-20000 J/m³.

In a more preferred aspect the present invention provides a modifiedrelease formulation wherein the pharmacologically active ingredient isreleased over a long period of time, for example longer than 3 hours incomparison to an immediate release tablet e.g., up to 24 hours, incomparison to an immediate release tablet Preferably thepharmacologically active ingredient is released from the formulationover 10 to 24 hours, for example over 18 to 22 hours.

Preferably the pharmacologically active ingredient has activity in thetreatment of cardiovascular diseases. In particular, thepharmacologically active ingredient is a beta-blocking adrenergic agentsuch as metoprolol or a pharmaceutically acceptable salt thereof.

In yet another aspect the invention provides a modified releasemetoprolol formulation including:

-   a) a metoprolol core comprising metoprolol or a pharmaceutically    acceptable salt thereof and optionally one or more pharmaceutically    acceptable excipients; and-   b) a film coat as defined above.

In a preferred aspect the core comprising metoprolol or apharmaceutically acceptable salt thereof includes a plurality of beadswhich comprise metoprolol or a pharmaceutically acceptable salt thereofand optionally one or more pharmaceutically acceptable excipientswherein each of the beads is coated with a film-coat as defined above.Preferably, the beads have an inert core as described previously.

Suitable pharmaceutically acceptable salts of metoprolol include thetartrate, succinate, fumarate or benzoate salts and especially thesuccinate salt. The S-enantiomer of metoprolol or a salt thereof,particularly the benzoate salt or the sorbate salt, may also be used.

Eudragit® NE30D is an ethyl acrylate/methyl methacrylate copolymer inwhich the ethyl acrylate concentration is about 67 mol %.

It was surprisingly found that the film coating of the present inventioncould be made with low amounts of surface active agents and that such acoating exhibited stability over time. The surface active agent(surfactant) can act as a stabilizer.

Suitably the amount of surface active agent used in a film coatingdispersion is in the amount less than 1.3%, e.g., 1.0, 0.9, 0.8, 0.7,0.6, 0.5, 0.4, 0.3, 0.2, or 0.1%, by weight of the dispersion. In oneembodiment, the surface active agent is in a range from 0.001-1.0% byweight of the dispersion. In another embodiment, the surface activeagent is in a range from 0.01-0.8% by weight of the dispersion. In yetanother embodiment, the surface active agent is in a range from 0.1-0.5%by weight of the dispersion.

Suitably the amount of surface active agent present in the film coat isless than 5.4% by weight of the weight of the film coat, e.g., less than5.0, 4.5, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.5, 0.1, 0.01, or 0.001% byweight of the weight of the film coat. In one embodiment, the surfaceactive agent in the film coat is in a range from 0.01-5.0% by weight ofthe weight of the film coat. In another embodiment, the surface activeagent is in a range from 0.1-4.0% by weight of the weight of the filmcoat. In yet another embodiment, the surface active agent is in a rangefrom 1.0-3.0% by weight of the weight of the film coat

Suitably the amount of surface active agent present in the dispersion isless than 5.6%, e.g., less than 5.0, 4.5, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0,0.5, 0.1, 0.01, or 0.001%, based on the dry weight of the film coatingcomponents.

Examples of suitable surface active agents\stabilizers include:

-   a nonionic surfactant, like sorbitan esters (Span series);    polysorbates (Tween series);-   polyoxyethylated glycol monoethers (like the Brij series);    polyoxyethylated alkyl phenols (like the Triton series or the Igepal    series); alkyl glucosides (e.g., dodecylmaltoside); sugar fatty acid    esters (e.g., sucrose laurate); saponins; etc: or mixtures thereof;-   ampholytic surfactants, like betaines;-   anionic surfactants, like sulphated fatty alcohols eg sodium    dodecylsulphate SDS; sulphated polyoxyethylated alcohols; others    like dioctyl sulphosuccinate; bile salts (e.g., dihydroxy bile salts    like sodium deoxycholate, trihydroxy bile salts like sodium    glycocbolate, etc); fusidates (e.g., sodium dihydrofusidate); etc    cationic surfactants, like ammonium compounds;-   soaps, fatty acids, and lipids and their salts, like alkanoic acids;    (e.g., octanoic acid, oleic acid); monoglycerides (eg monolein),    phospholipids which are neutral or positively or negatively charged    (eg dialkyl phosphatidylcholine, dialkyl phosphatidylserine, etc).

More preferably the surface active agent is a nonionic surfactant. Mostpreferably the surface active agent is nonoxynol 100.

Optionally, other different excipients can be included in theformulation by methods known to those skilled in the art, such aslubricants, plasticizers, etc.

Suitably the water-containing liquid comprises water and a watermiscible organic liquid for example lower alkanols e.g. ethanol,propanol or isopropanol. From a safety point of view it is preferredthat the proportion of the organic is kept to a minimum but smallamounts are tolerable for example in the range of 0 to 20% by volume.Preferably the liquid is water.

The film-coating composition is particularly suitable for use as anaqueous film-coating composition wherein the film-coat is applied usingwater as the liquid. This process is particularly advantageous as itnegates the need to use environmentally unacceptable organic solvents,some of which also present processing problems due to theirinflammablility, while also eliminating many of the problems experiencedwith aqueous coatings described above.

In another aspect the present invention provides processes for thepreparation of the film-coating composition. Therefore, there isprovided a process for the preparation of a film-coating compositioncomprising mixing together the acrylic polymer dispersion, vinyl acetatepolymer dispersion, the stabilizer and the liquid at a temperature inthe range of 10 to 100° C.

In one embodiment of the process the acrylic polymer dispersion, thestabilizer, the surface active agent and the liquid, are mixed at roomtemperature.

Suitably mixing is achieved by methods such as stirring or shaking butother methods of homogenization known to those skilled in the art may beused.

In another aspect the present invention provides a process for filmcoating a pharmaceutical core wherein a film coating composition asdefined above is applied to a core. Preferably the film coatingcomposition is applied by spraying for example in a fluidised bed withtop spray or bottom spray techniques. Other coating methods used arecoating in standard coating pans with perforated pans, Accela-cota,immersion swords, Glatt, or immersion tubes as described in “Theory andPractice in Industrial Pharmacy” edited by Lachman, published by Lea andFeabiger 1986 3^(rd) edition.

In another aspect the invention provides a process to prepare a filmcoat as defined above comprising removing the liquid from a film coatingcomposition as defined above. Suitably the liquid is removed byevaporation for example by spray drying for example in a fluidised bed.

In yet another aspect the invention provides a process to prepare aformulation as defined above comprising coating a pharmaceutical core asdefined above with a film coating composition as defined above.

In a further aspect the invention provides a process to prepare aformulation in which the pharmacologically active ingredient is providedas a plurality of beads as defined above comprising coating theplurality of beads with a film-coating composition as defined above.

EXAMPLES

The following examples are non-limiting and are given by way ofillustration only. It will be appreciated by those skilled in the artthat the examples are to be looked upon as guidelines, and the inventionis not restricted to the exemplified compositions. A wide range ofcombinations is possible to give film coatings having the necessaryproperties required for each specific application.

Example 1

Preparation of Coated Metoprolol Succinate Pellets From NE30D/GMS/PS80.The Preparation Contains:

-   5.0 GMS+190 g water+1 g Polysorbate80+25 g cold water+334.6 g NE 30D-   (giving GMS/particle ratio approximately 5% and PS80/GMS ratio    approximately 20%)

The mixture of 5 g GMS, 1 g Polysorbate 80 and 190 g water was heated to60-63° C. while stifling. After 30 minutes (min) of homogenizing, themixture was cooled initially by adding 25 g cold water and then furthercooled in a cold-water bath until the temperature was below 35° C. Thesolution was then slowly poured into the NE30D dispersion while gentlystirring. Stirring was continued until the start of coating.

The coating was performed in a small-scale coater. Coating was performedby pouring 400 g of metoprolol succinate pellets (size fraction 0.400.63mm, with inert silicon dioxide cores) into the coater and the solutionsprayed on to it. The coated pellets where cured afterwards in a 60° C.heat cabinet for one (1) hour.

The coating yield was 92%. The drug content for the pellets aftercoating: 630 mg/g pellets. The coated pellets where then analysedregarding drug content and release profile. Dissolution tests wereconducted in USP 23 paddle apparatus equipped with flow-through cells(at 37° C., 100 rpm, 500 ml sodium phosphate buffer solution, pH 6.8).The release from the coated pellets and tablets was measured onlineusing an UV-spectrophotometer (Lambda 2, Perkin-Elmer) at 274 nm Theamount of drug release was calculated on the determined drug content.TABLE 1 7 days 7 days 7 days 14 days 14 days 14 days Release Zero incli- in cli- in cli- in cli- in cli- in cli- time (h) value mate 1 mate2 mate 3 mate 1 mate 2 mate 3 1 0.3 0.3 0.4 0.5 0.3 0.3 0.4 2 0.4 0.30.4 0.6 0.3 0.3 0.5 3 0.4 0.4 0.5 0.7 0.4 0.4 0.6 4 0.4 0.4 0.5 0.87 0.40.5 0.9 6 0.5 0.6 0.8 2.4 0.5 0.8 4.1 8 0.6 1.0 1.7 6.9 0.9 2.3 11.4 101.2 2.1 4.4 13.5 2.3 6.9 20.6 12 2.6 5.9 13.6 21.4 7.7 19.6 30.5 14 8.219.8 35.4 30.1 26.6 42.4 40.8 16 23.6 44.7 58.4 39.6 52.9 62.3 51.1 1844.3 64.8 72.7 49.4 70.4 75.1 60.9 20 61.1 76.2 81.2 58.6 80.1 82.7 69.2Zero value: release value after curing (60° C./50% relatively humidity(r.h.) during 60 min).Climate 1; 25° C./60% r.h.Climate 2; 30° C./60% r.h.Climate 3; 40° C./75% r.h.Each value is a mean value of two analyses.Results

The results show how the release profiles change with time and storageconditions. Samples stored in higher temperatures and humidity tended tohave a more linear profile compared to those samples in lowertemperatures and humidity. This change during storage is most likely dueto migration of surfactants, especially polysorbate 80, up to surfaceleading to increased permeability.

Example 2

Preparation of Coated Metoprolol Succinate Pellets From NE30D/GMSSolution. The Preparation Contains:

-   3.0 g GMS+150 g water+25 g cold water+200 g NE 30D-   (giving GMS/particle ratio approximately 5% and film amount/pellets    ratio approximately 20%)

The mixture of 3 g GMS and 150 g water was heated to 60-63° C. whilestirring. After 30 minutes the mixture was cooled initially by adding 25g cold water and then further cooled in a cold-water bath until thetemperature was below 35° C. The solution was then slowly poured intothe NE30D dispersion while gently stirring. Stirring was continued untilthe start of coating.

The coating was performed in a small-scale coater. Coating was performedby pouring 350 g of metoprolol succinate pellets (size fraction0.40-0.63 mm, with inert silicon dioxide cores) into the coater and thesolution sprayed on to it. The pellets where cured afterwards in a 60°C. heat cabinet for 6 min. The coating yield was 90%. The drug contentfor the pellets after coating: 659 mg/g pellets.

The coated pellets were then stored in a climate cabin at differenttemperatures and humidity for one and two weeks. The coated pelletswhere then analysed regarding drug content and release profile.

Dissolution tests were conducted in USP 23 paddle apparatus equippedwith flow-through cells (at 37° C., 100 rpm, 500 ml sodium phosphatebuffer solution, pH 6.8). The release from the coated pellets andtablets was measured online using an UV-spectrophotometer Lambda 2,Perkin-Elmer) at 274 nm. The amount of drug release was calculated onthe determined drug content.

Results

The release profile was analysed for the coated pellets after finaldrying (curing) and after 7 and 14 days in three different climates, seetable 2. TABLE 2 Release 7 days 7 days 7 days 14 days 14 days 14 daysTime Zero in cli- in cli- in cli- in cli- in cli- in cli- (h) value mate1 mate 2 mate 3 mate 1 mate 2 mate 3 1 0.49 0.3 0.3 0.2 0.3 0.2 0.3 21.6 0.76 0.5 0.3 0.68 0.3 0.6 3 3.7 1.9 1.1 0.4 1.4 0.7 0.8 4 6.98 3.92.3 0.7 2.8 1.6 1.2 6 17.4 13.3 10.4 3.5 10.9 9.4 3.7 8 27.9 25.5 24.813.85 24.1 25 13 10 37.6 36.1 37.2 27.6 35.4 38.3 25.8 12 47.2 46.1 48.340.5 45.8 49.9 38.6 14 56.5 55.7 58.5 52.35 55.6 60.4 50.4 16 65.1 64.5567.3 62.2 64.6 69.1 60.4 18 72.5 72.4 74.6 69.8 72.1 75.7 68.1 20 78.377.8 80.2 75.4 78.1 80.8 74Climate 1; 25° C./60% r.h.Climate 2; 30° C./60% r.h.Climate 3; 40° C./75% r.h.Each value is a mean value of two analysis.Results

The results shows similar profiles after 7 and 14 days in the threedifferent climates. No migration can be seen in Example 2.

Example 3 Tablets Made From the Coated Pellets of Example 2

Preparation of 950 Tablets

The coated pellets where compressed into tablets by conventionaltechniques. During this process other agents where added, fillers Aviceland Sodium stearyl fumarate (Pruv®) to give acceptable compressioncharacteristics of the formulation, e g hardness and weight.

136.9 g of coated pellets (from experiment 2) were mixed with 205.3 g ofmicrocrystalline cellulose (Avicel PH 102 (course), FMC) in a Turbulamixer (W. A. Bachofen, Switzerland) for 4 minutes. After this time 0.68g Sodium stearyl fumarate was added and mixing was continued for anotherminute. The tablet weight was calculated to be 361 mg.

Tablets of pellets were compacted in a rotary tablet machine (six (6)punch press, Korch PH 106, Germany). The press was equipped withconcave-faced punches with a diameter of 10 mm. The force used wasapproximately 4 KN. The hardness of the tablets were approx. 142 N (meanvalue of ten measurements). After the tablets have been sorted out byweight, they were put in the same cabin as the coated pellets fromExample 2, and samples were taken after one and four weeks. See Table 3.

The release profile of the tablets was then analysed.

Dissolution tests were conducted in USP 23 paddle apparatus equippedwith flow-through cells (at 37° C., 100 rpm, 500 ml sodium phosphatebuffer solution, pH 6.8). The release from the coated pellets andtablets was measured online using an UV-spectrophotometer (Lambda 2,Perkin-Elmer) at 274 nm. The amount of drug release was calculated onthe determined drug content. TABLE 3 Release 7 days 7 days 7 days 28days 28 days 28 days Time Zero in cli- in cli- in cli- in cli- in cli-in cli- (h) value mate 1 mate 2 mate 3 mate 1 mate 2 mate 3 1 15 19 1913 19 18 17 2 27 34 34 29 35 32 32 3 37 44 43 41 45 42 43 4 45 52 51 4952 50 51 6 58 62 61 60 63 61 62 8 67 70 69 68 71 70 69 10 74 77 75 74 7776 75 12 79 82 80 79 83 82 79 14 84 87 85 84 87 87 83 16 87 91 89 87 9190 86 18 90 94 92 90 93 93 89 20 93 97 94 93 95 96 91Each value is a mean value of two analysis.Climate 1; 25° C./60% r.h.Climate 2; 30° C./60% r.h.Climate 3; 40° C./75% r.h.Results

The results showed no major change in the release profile during storagein the different climates.

1. A film coating composition suitable for use in coating pharmaceuticalformulations, wherein the composition comprises a dispersion comprising:a) an ethyl acrylate/methyl methacrylate copolymer; b) an anti-stickingagent, which is glyceryl monostearate (GMS); c) a surface active agentswherein the surface active agent is present in an amount less than 1.3%by weight of the dispersion; and d) a water-containing liquid, whereinthe dispersion does not contain a vinyl acetate polymer.
 2. A film coatcovering a pharmaceutical core, wherein the core comprises apharmacologically active ingredient and optionally one or morepharmaceutically acceptable excipients, and wherein the film coatcomprises: a) an ethyl acrylate/methyl methacrylate copolymer; b) ananti-sticking agent, which is glyceryl monostearate (GMS); and c) asurface active agent, wherein the surface active agent is present in anamount of less than 5.4% by weight of the weight of the film coat, andwherein the film coat has been deposited on the pharmaceutical core froma water-containing liquid and does not contain a vinyl acetate polymer.3. A pharmaceutical formulation comprising: a) a pharmaceutical corecomprising a pharmacologically active ingredient and optionally one ormore pharmaceutically acceptable excipients, and b) a film coat coveringthe pharmaceutical core, wherein the film coat comprises: i) an ethylacrylate/methyl methacrylate copolymer; ii) an anti-sticking agent,which is glyceryl monostearate (GMS); and iii) a surface active agent,wherein the surface active agent is present in an amount of less than5.4% by weight of the weight of the film coat, and wherein the film coathas been deposited on the pharmaceutical core from a water-containingliquid and does not contain a vinyl acetate polymer.
 4. A pharmaceuticalformulation comprising a plurality of beads containing apharmacologically active ingredient and optionally one or morepharmaceutically acceptable excipients, wherein each of the beads iscoated with a film coat comprising: a) an ethyl acrylate/methylmethacrylate copolymer; b) an anti-sticking agent, which is glycerylmonostearate (GMS); and c) a surface active agent, wherein the surfaceactive agent is present in an amount of less than 5.4% by weight of theweight of the film coat, and wherein the film coat has been deposited onthe beads from a water-containing liquid and does not contain a vinylacetate polymer.
 5. The formulation according to claim 3 or 4, whereinthe formulation is a modified release formulation.
 6. The formulationaccording to claim 5, wherein the pharmacologically active ingredienthas activity in the treatment of cardiovascular diseases.
 7. Theformulation according to claim 6, wherein the pharmacologically activeingredient is a beta-blocking adrenergic agent.
 8. The formulationaccording to claim 7, wherein the pharmacologically active ingredient ismetoprolol or a pharmaceutically acceptable salt thereof.
 9. Theformulation according to claim 8, wherein the metoprolol salt is atartrate, succinate, fumarate, or benzoate salt.
 10. The composition asclaimed in claim 1, wherein the liquid is water.
 11. A process for thepreparation of a film coating composition according to claim 1, theprocess comprising mixing together the ethyl acrylate/methylmethacrylate copolymer, the anti-sticking agent, the surface activeagent, and the liquid at a temperature in the range of 10 to 100° C. toform a dispersion.
 12. A process for the preparation of a pharmaceuticalformulation as claimed in claim 3, comprising coating the pharmaceuticalcore with a film coating composition, wherein the composition comprisesa dispersion comprising: a) an ethyl acrylate/methyl methacrylatecopolymer; b) an anti-sticking agent, which is glyceryl monostearate(GMS); c) a surface active agent wherein the surface active agent ispresent in an amount less than 1.3% by weight of the dispersion; and d)a water-containing liquid, and wherein the dispersion does not contain avinyl acetate polymer.
 13. A process for the preparation of apharmaceutical formulation according to claim 4, the process comprisingcoating each of the plurality of beads with a film coating composition,wherein the composition comprises a dispersion comprising: a) an ethylacrylate/methyl methacrylate copolymer; b) an anti-sticking agent, whichis glyceryl monostearate (GMS); c) a surface active agent wherein thesurface active agent is present in an amount less than 1.3% by weight ofthe dispersion; and d) a water-containing liquid, and wherein thedispersion does not contain a vinyl acetate polymer.
 14. The filmcoating composition according to claim 1, wherein the ethylacrylate/methyl methacrylate copolymer is Eudragit® NE30D.
 15. The filmcoat according to claim 2, wherein the ethyl acrylate/methylmethacrylate copolymer is Eudragit® NE30D.
 16. The pharmaceuticalcomposition according to claim 3, wherein the ethyl acrylate/methylmethacrylate copolymer is Eudragit® NE30D.